Cytokines generally stimulate proliferation or differentiation of cells of the hematopoietic lineage or participate in the immune and inflammatory response mechanisms of the body. The interleukins are a family of cytokines that mediate immunological responses. Central to an immune response is the T cell, which produces many cytokines and plays a role in adaptive immunity to antigens. Cytokines produced by the T cell have been classified as type 1 and type 2 (Kelso, A. Immun. Cell Biol. 76:300-317, 1998). Type 1 cytokines include IL-2, IFN-γ, LT-α, and are involved in inflammatory responses, viral immunity, intracellular parasite immunity and allograft refection. Type 2 cytokines include IL-4, IL-5, IL-6, IL-10 and IL-13, and are involved in humoral responses, helminth immunity and allergic response. Shared cytokines between Type 1 and 2 include IL-3, GM-CSF and TNF-α. There is some evidence to suggest that Type 1 and Type 2 producing T cell populations preferentially migrate into different types of inflamed tissue.
IL-21 has been shown to be a potent modulator of cytotoxic T cells and NK cells. (Parrish-Novak, et al. Nature 408:57-63, 2000; Parrish-Novak, et al., J. Leuk. Bio. 72:856-863, 202: Collins et al., Immunol. Res. 28:131-140, 2003; Brady, et al. J. Immunol. 172:2048-58, 2004.) T cell responses include enhancement of primary antigen response as modulation of memory T cell functions.
In murine studies, IL-21 potentiates the maturation and effector function of NK cells and promotes T cell activation in response to alloantigen (Kasaian et al., Immunity 16:559-569, 2002. As a cytokine which limits NK cell expansion and promotes activation of murine CD8 T cells, IL-21 is believed to play a role in the transition from innate to adaptive immunity (Kasaian, supra, 2002). Among CD4 T cells, IL-21 has been described as both a Th1 (T helper 1) cytokine which upregulates the expression of genes associated with innate immunity (Strengell et al., J. Immunol. 170:5464, 2003) as well as a Th2 cytokine that inhibits the differentiation of naïTh cells into IFN-gamma-producing Th1 cells (Wurster et al., J. Exp. Med. 196:968, 2002). The effects of IL-21 in the development of innate immunity and CD4 Th responses are well-characterized (Strengell supra, 2003; Strengell et al., J. Leukoc. Biol. 76:416, 2004), but its role in the antigen-specific CD8+ T cell response, particularly in humans, had not been fully explored. The present invention provides methods for inducing a high affinity CD8 response against self antigens, which are represented increasingly as potential immune targets in cancer immunotherapy demonstrate a significant role for IL-21 in antigen-specific anti-tumor strategies. Thus, the present invention provides methods for administering IL-21 as an adjuvant in tumor vaccines and ex vivo expansion of tumor antigen-specific cytotoxic T cells for use in adoptive immunotherapy. The present invention also provides methods for administering IL-21 as an adjuvant for vaccines and ex vivo expansion of antigen-specific cytotoxic T cells in general against viruses, and other target antigens. These and other uses should be apparent to those skilled in the art from the teachings herein.